TW200418455A - Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration - Google Patents

Abstract

Methods of treating, preventing and/or managing macular degeneration are disclosed. Specific embodiments encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or surgery. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

200418455 发明 Description of the Invention: This application claims the benefit of US Provisional Application No. 60 / 422,900, filed on October 31, 2002, the contents of which have been fully incorporated herein by reference. [Technical field to which the invention belongs] The present invention relates to a method for treating, preventing and treating macular degeneration (MD) and related syndromes, which comprises administering a selective cytokine inhibitory agent, which can be administered alone or in combination with known therapies. The invention also relates to pharmaceutical compositions and medications. In particular, the invention includes the use of selective cytokine inhibitory agents in combination with surgical intervention and / or other standard therapies for macular degeneration. [Previous Technology] Macular Degeneration Pathology Macular Degeneration (MD) is an eye disease that damages central vision by harming the macula. The macula is part of the retina and is a thin layer of nerve cells located mainly inside the eyeball. The nerve cells in the retina detect the light and send it to the brain to tell the brain what the eyes see. The macula is close to the center of the retina behind the eyeball, and the animal uses it to focus on the things in front of it to get a clear central image. The rest of the retina provides side (peripheral) images. There are two types of MD: atrophy ("dry") and exudate ("wet"). Riordan-Eva, P., Eye, in Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). Ninety percent of patients are dry and only 10% are wet. However, up to 90% of wet patients may be blind. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18: 60-64 (1998). Macular degeneration causes choroidal neovascularization (CNVM) and / or retinal pigment epithelium (RPE) geometry in eyes with choroidal warts. Shrink. Bird, 89179 200418455 A.C., Surv. Ophthamol. 39: 367-74 (1995). Choroidal fatigue is small round white and yellow dots in the basal area outside the retina. Other symptoms of MD include detachment of RPE (PED) and discoid scar tissue under the macula. Algvere, P.V., Acta Ophthalmologica Scandinavica 80: 136-143 (2002). Choroidal neovascularization is a problem related to many retinal diseases, but it is still mainly related to MD. CNVM is characterized by abnormal blood vessels growing from the choroid (the vascular-rich tissue layer immediately below the visual omentum) and extending to the retinal layer. These new blood vessels are extremely fragile and easily ruptured, causing blood and body fluids to flow into the retinal layer. When a blood vessel leaks, it can interfere with delicate retinal tissue and cause vision damage. The severity of the symptoms depends on the size of the CNVM and how close it is to the macula. The patient's symptoms may be very mild, such as blurred vision or distorted vision or more severe, such as central blind spots. Patients with choroid warts and possibly pigmented abnormalities but without CNVM or geometric atrophy are usually diagnosed with age-related macular degeneration (ARM). See above. The histopathology of ARM and MD is characterized by the continuous deposition of a layer of fine-grained material inside the Bruch's membrane at the base of RPE cells. Sarks, J.P., et al., Eye 2 (Pt. 5): 552-77 (1988). These basal deposits are considered to be the result of continuous RPE phagocytosis or accumulation of waste from the outer layers of photoreceptors. Basement deposits result in thicker Bruch membranes and reduced permeability. There is a hypothesis that a decrease in water permeability will impair nutrient exchange, accumulate water, and promote the development of soft choroid warts and PED, and eventually cause RPE cells to shrink. See above. However, the current overall understanding of ARM and MD pathology is incomplete, Cour, M., et al., Drugs Aging 19: 101-133 (2002). 89179 200418455 Because MD occurs in old age and this group grows rapidly, MD has become a major economic and social issue. Macularity is the most common cause of vision loss in people over 60 in developing countries. Macular degeneration has caused 1.7 million Americans to lose sight and 11 million others to be at risk. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18: 60-64 (1998). There is no known cure. Rhoodhooft, J., Bull. Soc. Beige Ophtalmol. 276: 83-92 (2000). Therefore, there is an urgent need for an effective method for treating MD. Treatments for age-related macular degeneration Until now, laser-induced coagulation has been the only treatment routinely used for MD, which only provides a moderate therapeutic effect. Laser photocoagulation is a type of laser surgery that uses a focused beam to burn small areas of the retina and abnormal blood vessels beneath the macula. Cautery causes infectious tissue, seals blood vessels, and prevents the macula from leaking. Laser photocoagulation is effective only in patients with wet MD. In addition, laser photocoagulation is only available to about 13% of their patients. Joffe, L. et al. International Ophthalmology Clinics 36 (2): 99-116 (1996). Laser photocoagulation does not cure wet MD, but it sometimes slows or prevents central vision loss. However, without treatment, vision loss due to wet MD will continue to develop until the patient's residual vision is lost. The most serious disadvantage of laser surgery is that it can damage some of the macular nerves that react with light and cause some vision loss. Occasionally, vision loss due to surgery is as severe or more severe than when it is untreated. However, in some patients, the initial vision loss after laser surgery can prevent vision deterioration over time. Verteporfin has recently been used to treat wet MD. Cour, M., et al. 89179 200418455, Drugs Aging 19: 101-133 (2002). Fitphen is a vascular blocking photoreactive dye that is administered via injection. The dye moves towards the blood vessels that cause vision loss and is activated by a non-cauterizing flash that enters the eye in the presence of oxygen. Fitphen is mainly delivered into the blood plasma via lipoproteins. Activated fitterfin produces a highly reactive, short-lived single oxygen and reactive oxygen free radical, causing local damage to the neovascular endothelium. As a result, blood vessels are occluded. It is known that injured endothelium will release procoagulant and vasoactive factors through lipid-oxidase (leukotrienes) and cyclooxygenase (arachidoids such as prostamin) pathways, causing platelets to coagulate and form fibrin clot Blocks and vasoconstriction. Fitphen seems to tend to accumulate in new blood vessels, including choroidal new blood vessels. However, animal models show that Fitterfin also accumulates in the retina. Therefore, administration of Fitphen may damage retinal structures, including the retinal pigment epithelium and the outer nuclear layer of the retina. Another method currently used to treat MD is a drug-based antiangiogenic therapy. Cour, M., et al. Drugs Aging 19: 101-133 (2002). However, the first clinical trial using an anti-angiogenic agent: interferon-α failed to effectively treat MD, with high side effects. Arch. Ophthalmol. 115: 865-72 (1997). Intravitreal injection of triamcinolone is reported to suppress CNVM stigmatized by lasers in monkeys, but cannot prevent MD patients from severely losing their vision within one year in randomized trials. Gillies, M.C., et al., Invest. Ophthalmol Vis. Sci. 42: S522 (2001). Many other anti-angiogenic drugs have reached different stages of development for patients with MD, including vasostatic steroids (eg, anecortave acetate, Alcon drug) and vascular epithelial growth factor (VEGF) antibodies or Its fragment. Guyer, D.R., et al., Invest. 89179 200418455

Ophthalmol. Vis. Sci. 42: S522 (2001). One of the VEGF antibodies is rhuFab. Other new drugs used to treat MD include EYE101 (Eyetech), LY333531 (Eli Lilly), Miravant and RETISERT implants (Bausch & Lomb) Allows steroids to penetrate the eyes for three years. Although new and effective therapies for MD and related macular degeneration are being explored, there are no effective treatments. Therefore, there is a need in the art for an effective treatment for MD. Selective cytokine inhibitory agents A drug called SelCIDsTM (Celgene) or selective cytokine inhibitory agents has been synthesized and tested. These compounds strongly inhibit the production of TNF-α, and have a moderate inhibitory effect on LPS-induced ILlp and IL12. L.G. Corral, et al. Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999). Selective cytokine inhibitory agents are also characterized by their potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes found in human spinal cord and lymphoid cells. This enzyme plays an important role in regulating cell activity, it degrades cAMP, a ubiquitous second messenger, and maintains a low intracellular concentration. See above. Inhibition of PDE4 activity will result in an increase in cAMP concentration, which can regulate the cytokines emitted by LPS, including inhibition of TNF-α production in monocytes and lymphocytes. [Summary of the Invention] The present invention includes a method for treating and preventing macular degeneration, which comprises administering to a patient in need thereof a medically or prophylactically effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt or solvate thereof. , Hydrate, Li 89179 200418455 17 :: = shaped inclusion compound or prodrug. The present invention also includes a selective cytokine-inhibitory agent or a medicament for treating drugs; ==, solvate, hydrate, stereoisomer, and peony. Examples include selective cells. Salts, solvates, hydrates, stereo

Dimorphic inclusion compounds or prodrugs, and others suitable for the treatment or prevention of MD injections; and 5 use, such as (but not limited to): steroids, photosensitizers, whole ::, antioxidants, interferons, yellow throat Derivatives, growth hormones,

疒 -nature: Hematopoietic factors, modulators of neovascularization, anti-VEGF vaso-expansive compounds, or combinations thereof. Hormone "compounds or anti-antibiotics" Another specific embodiment includes treatment, prevention, or treatment should include the administration of a medically or prophylactically effective amount to a patient in need thereof Acceptable salts, solvents, hydrates, stereoisomers, osmium inclusion compounds or prodrugs in combination with therapies traditionally used to treat or prevent MD, such as (but not limited to): surgical intervention (eg: Laser photocoagulation therapy and photodynamic therapy). The present invention also includes a pharmaceutical combination unit dosage form and set suitable for treatment, prevention and / or treatment, which comprises a selective cytokine inhibitory agent or a pharmaceutically acceptable agent thereof. Salts, solvates, hydrates, stereostructures, osmium inclusion compounds or prodrugs. [Embodiments] 89179 -10-200418455 The first embodiment of the present invention includes a method for treating and preventing MD, which includes Administer a medically or prophylactically effective amount of a selective cytokine-inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate thereof to a patient in need thereof (eg, mammals such as humans) Substances, stereoisomers, clathrates or prodrugs. The present invention also relates to methods for treating or preventing specific MD and related symptoms, including (but not limited to) · atrophic (dry) MD, leakage Type (wet) MD, age-related macular degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED), and retinal pigment epithelial atrophy (RPE). The term "macular degeneration" ( MD) includes all macular degenerative diseases regardless of the patient's age, but some macular degenerative diseases are more common in certain age groups. They include (but are not limited to): Best's disease or yolk type (most commonly around 7 years old) The following patients); Stargardt's disease, juvenile macular dystrophy, or basal macula (most commonly in patients aged 5 to 20 years); Behfs disease, Sorsb / s disease), Doyne's disease, or honeycomb dystrophy (most common in patients about 30 to 50 years of age); macular degeneration associated with aging (most common in patients about 60 or older) The causes of MD include (but are not limited to): genetic, physical trauma, diseases (such as: diabetes) and infections, such as: bacterial infections (such as: leprosy, specifically ENL). Another specific embodiment of the present invention includes A method of treating MD, which comprises administering to a patient in need of such treatment a preventively effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt thereof, solvate, hydrate, stereoisomer, cage Inclusion compound or prodrug. 89179 -11-200418455 Another embodiment of the present invention includes a pharmaceutical composition comprising a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate thereof. , Stereoisomers, clathrates or prodrugs and optional carriers. The present invention also includes a single unit dosage form, which comprises a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereostructure, clathrate or prodrug thereof, and can be selected as required The carrier. Another embodiment of the present invention includes a kit comprising a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, osmium inclusion compound or Prodrug pharmaceutical composition. The invention also includes kits comprising a single unit dosage form. The set included in the present invention may further contain other active agents. Specific kits include Amsler gHd suitable for the detection or diagnosis of MD. Without being limited by theory, it is believed that some selective cytokine inhibitory agents and other medicines that can be used to treat the symptoms of MD can treat or treat MD in a complementary or pro-active manner. Because of Λ, a specific embodiment of the present invention includes a method for obstetrics, prevention, and / or treatment of MD, which includes electricity for such needs = administration of a medical or preventive effective amount of a selective cytokine ㈣: medicament ^ medicine Acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs, and are medically or preventively effective. Examples of second active agents include (but are not limited to) traditionally used ^ 2 Agent. Pharmacy, such as: class alcohols, photosensitizers, integrin, = or prevention of interferon, lutein derivatives, growth hormone, chemotherapeutic system, dry 丨 Wang Yueqiu ^ because of the new Regulators of angiogenesis, anti-VEGF antibodies, prostaglandin 89891-12. 200418455 phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, and other visible elements such as the agents in Physician's Desk Reference 2003. Specific examples of the second active species include (but are not limited to) phenanthrene, priton, vasostatic steroids, gamma, interferon such as integrin, and antioxidative enzymes. Both j and g can be tested. The invention also includes pharmaceutical compositions, single unit dosage forms and kits, which include selective cytokine inhibitory agents or their pharmaceutically acceptable salts, :: '! Hydrates, hydrates, stereoisomers , Clathrate or prodrug with f-th active agent. For example, the kit may include a compound of the present invention and a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrophil, a regulator of neoangiogenesis, an anti-angiogenic effect, -VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, or combinations thereof 'or other drugs that can relieve or reduce: MD symptoms. It is believed that certain selective cytokine inhibitory agents can reduce or eliminate the side effects associated with the administration of agents for the treatment of MD, in order to increase the dose to the patient and / or improve the patient's adaptability. Therefore, other specific embodiments of the present invention include a method for reversing, reducing or avoiding side effects associated with receiving a second active agent in patients with MD, including administering a medically effective amount of selective cytokine suppression to patients in need Sex drugs or their medicinal access: < Salts, solvates, hydrates, stereoisomers, clathrate prodrugs. 3

As discussed elsewhere in this article, MD symptoms can be treated with surgical interventions such as (but not limited to): light or laser therapy, radiation therapy, retina Z 89179 -13- 200418455 prime epithelial transplantation and omental center displacement . Without being bound by theory, salty crops, such traditional therapies combined with selective cytokine inhibitory agents make them extremely effective. Accordingly, the present invention includes a method of treating, preventing, and / or treating a method that includes administering a selective cytokine inhibitory agent or a pharmaceutically acceptable method during or after surgical intervention or other traditional non-drug therapy. Salts, solvates, hydrates, stereoisomers :, hydrazone: clathrates or prodrugs. / Hormone-inhibiting Hua Hua Dian Tian The compounds used in the present invention include racemic, pure stereoisomerism, and high stereoselectivity cytokine inhibitory agents, and stereoisomerism with selective cytokinesis inhibitory activity. And pure enantiomeric compounds and their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, hydrazones: clathrates and prodrugs. A preferred compound for use in the present invention is a known selective cytokine inhibitory agent, Intestine TM, from Celgene®, New Jersey. The term "selective cytokine inhibitory agents," and "SelCIDs ™," as used herein and unless otherwise stated, includes small molecule agents, such as peptides, proteins, nucleic acids, oligosaccharides, or other large molecules Small organic molecules. Preferred compounds inhibit TNF_a production. The compound also has a moderate inhibitory effect on βν and IL12 induced by Lps. Even better, the compound is a potent inhibitor of pDE4. Specific examples of selective cytokine inhibitory agents include, but are not limited to, cyclic imines, which are disclosed in U.S. Patent Nos. 5,605,914 and 5,463,063; 4 Patent Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and Cycloalkylamines and cycloalkyl nitriles of 6,518,281; US patents 89179 -14- 200418455, arylamines of 5,801,195, 5,736,570, 6,046,221, and 6,284,780 (eg, a specific embodiment is N _Benzamyl winteramido_3- (3 ', 4, _dimethydonyl) -propanamine), imines / fermented amines_ and alcohols (for example: 3 -g tamate imide Phenyl-3- (3 ', 4'-dimethoxyphenyl) propyl ",), which is disclosed in U.S. Patent No. 5,703,098; succinimide and maleimide (for example, 3- ( 3,4,5,6, _tetrahydroacetic acid imino) -3- (3 '', 4, '-dimethoxyphenyl) propionic acid methyl ester), disclosed in U.S. Patent No. 5,658,940 ; Alkylimido hydroxamic acids substituted with imino and amidino groups, which are disclosed in US Patent Nos. 6,214,857 and WO 99/06041; substituted phenethyl sulfones, which are disclosed in US patents Case Nos. 6,011050 and 6, 〇20,358; Substituted imines (eg, 2-phthaloimino-3_ (3 ,, 4, -dimethoxyphenyl) propane), which are disclosed in the United States Patent No. 6,429,221; Substituted 1,3,4 · oxadiazoles (for example: 2- [1- (3 • cyclopentyloxy-4-methoxyphenyl) _2_ (1,3, 'fluorene Azole-2-yl) ethyl] -5-methylisoindole-i, 3-diketone), which is disclosed in US Patent No. 6,326,388; cyano and carboxy derivatives of substituted styrene (eg: 3,3-bis- (3,4-dimethoxyphenyl) propionitrile), which is disclosed in U.S. Patent Nos. 5,929,117,6,130,226, 6,262,101, and 6,479,554; 2-position via α- ( 3,4-Disubstituted phenyl) alkyl-substituted iso-4inolin-1-ones and isoxolinolin-1,3-diones substituted at the 4- and / or 5-position with nitrogen-containing groups , Which is disclosed in WO 01/34606; and fluorenyl hydroxamic acids substituted with imino and fluorenyl groups (eg, (3- (1,3-dioxoisoindolin-2-yl)) -3- (3-ethoxy-4-methoxyphenyl) propanamido) propionate, which is disclosed in WO 01/45702. Each of the patent cases and patent filings presented here, Yang 7F The subject has been incorporated herein by reference in its entirety. Other selective cytokine inhibitory agents are a synthetic chemical compound 89179 -15- 200418455. Typical examples include 3_ (u_dioxobenzochrysene Iso + Duo-2-yl) -3- (3-cyclopentyloxy-4-methoxyphenyl) propanamide and 3_ (ι, 3 · dioxo_4_azaisoisodinole 2-yl)- 3- (3,4-Dimethoxyphenyl) -propanamide. Other specific selective cytokine inhibitory agents belong to a class of non-polypeptide cyclic amidines, the disclosures of which are disclosed in U.S. Patent Nos. 5,698,579 and 5,877,200, both of which are fully incorporated herein by reference. Representative amines include compounds of the following formula: 0 H, 0 R \ / _ (fH ~ (C ^)-C-Rl2 R7 Η Η where η is 1, 2, or 3; R5 is adjacent extension Phenyl, unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of nitro, cyano, trifluoromethyl, ethyl, methyl, and propyl , Ethanoyl, carbamate, ethanoyloxy, carboxyl, hydroxy, amine, alkylamino, dialkylamino, fluorenylamino, alkyl with i to 10 carbon atoms, 1 Alkoxy groups of up to 10 carbon atoms, and _ groups; R7 is (i) phenyl or phenyl substituted by one or more substituents independently selected from the group consisting of: nitro, cyano Methyl, trifluoromethyl, ethyl, methyl, propyl, ethyl, carbamoyl, ethyloxy, carboxyl, hydroxy, amino, alkyl of 1 to 10 carbon atoms, Carbooxy group of 1 to 10 carbon atoms, and I group; (ii) benzyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: nitro , Chloro, trimethyl, ethyl, methyl, propyl , Acetamyl, carbamoyl, acetamyloxy, carboxyl, hydroxy, amine, alkyl of 1 to 10 carbon atoms, 1 to 89179 -16- 200418455 alkoxy of 1 carbon atom, and (Iii) fluorenyl; and (iv) benzyloxy; R12 is -OH, an alkoxy group of 1 to 12 carbon atoms, or

V R8 is fluorene or an alkyl group of 1 to 10 carbon atoms; and 10 wherein

R9 is hydrogen, an alkyl group of 1 to 10 carbon atoms ... c0r1G, or · s〇2R R10 is hydrogen, an alkyl group or phenyl group of 1 to 10 carbon atoms. Such clear compounds include, but are not limited to, 3-phenyl-2- (1-oxoisoindolin-2-yl) propionic acid; 3phenyl-2- (1-oxoisoindole Indolin_2_yl) propanamidin, 3-phenyl_3- (1-oxoisoindololinyl) propionic acid; 3-phenyl_3 ) Propanamide; 3- (4_methoxyphenyl) -3 oxo-isoisopropane-yl) propionic acid, 3 (4-methyl lactyl) _3 oxoisometyl) propionate Amine; ('methoxyphenylbu 3 ^ 1 · oxoisoindolinyl) propionic acid; methoxy-phenyloxo-1,3-dihydroisoindol-2-yl) propanamide ; 7 3- (3,4-monomethoxyphenyl) -3-Γ 1 t ,,, J (K-Isoindolin-2-yl) propanamide; 3- (3,4-di Ethoxyphenyl, ^^ oxoisoindolin-yl) propionic acid; 3- (1-oxoisoindolinline · 2 # a. Earth-ethoxy-4-methoxyphenyl) propene Acid formamidine 0,-(3-ethoxy-4-methoxyphenyl) propionic acid_ (3-propoxy-4-methoxyphenyl) propionic acid- (3-butoxy-4-methyl Oxophenyl) propanoic acid 3- (1-oxoisoindolinyl) _3 3- (1-oxoisoindolinyl) _3 3- (1-oxoisoindolinyl_2_yl) _3 89179 -17- 200418455 3- (1-oxygen Isoxolinolin-2-yl > 3- (3-propoxy-4-methoxyphenyl) propanamide; 3- (1-oxoisooxolin-2-yl) -3- ( 3-butoxy-4-methoxyphenyl) propanamide; 3 -_ (1-oxoisoxolinolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propane Formic acid methyl ester; with 3- (1-oxoiso4 丨 lar # -2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid methyl ester. Other clear choices Sexual cytokine inhibitory agents include imino and amidino-substituted alkanoyl isohydroxy fatty acids, which are disclosed in WO 99/06041, the disclosure of which is fully incorporated herein by reference. These compounds include (But not limited to): 〇rsA Yan 3 I, n-ch; s R〆 ^ R5 (CnH ^) — C—N-0-R4 R4 · Where each R1 and R2 are independent, they are hydrogen and low carbon number Alkyl, or R1 and R2 may form an o-phenylene, o-phenylene, or cyclohexene-1,2-diyl group, unsubstituted or independently selected from 1 to 4 respectively Substituent substitution in the group consisting of: nitro, cyano, trifluoromethyl, ethyl @ ayyl, methyl ethyl, propyl ethyl, ethyl ethyl, aminomethyl, ethyl ethyl, Carboxy Group, hydroxyl, amine, alkylamino, dialkylamino, fluorenylamino, alkyl of 1 to 10 carbon atoms, alkoxy and dentyl of 1 to 10 carbon atoms; R3 is 1 to 4 phenyl substituted by a substituent independently selected from the group consisting of the following: nitro, cyano, trifluoromethyl, ethyl, methyl, 89179 -18- 200418455 propyl Base, ethenyl, carbamoyl, ethenyloxy, compound, warp, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, 1 to 10 Alkylthio of carbon atom, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C4_C6_cycloalkylenemethyl, C3_Cl () _ alkylenemethyl, indanyloxy and halo ; R4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R is hydrogen or a radical of 1 to 6 carbon atoms; R5 is -CH2-, _CH2_CO_, -S02-, -S -Or _NHCO_; the value of η is 0, 1 or 2; and acid addition salts of compounds containing protonatable nitrogen atoms. Other specifically selective cytokine inhibitory agents useful in the present invention include, but are not limited to: 3- (3-ethoxy-4-methoxyphenyl) _ν_hydroxy-3- (1-oxoisoindole Indolinyl) propanamide; 3- (3-ethoxymethoxyphenyl) methoxy-3- (1-oxoisoindololinyl) propanamide; N-benzyloxy-3 · (3 · Ethoxy Winter Methoxyphenyl) -3 · phthaloiminoimidopropanamine; Ν-Benzyloxy-3_ (3 · Ethoxy Winter Methoxyphenyl) _3_ (3_ nitrate Phthalocyanine imino) propanamidin; N-benzyloxyK3-ethoxy_4-methoxyphenyloxoisoindolinyl) propanamidin; 3- (3-ethoxy- 4-methoxyphenyl) _N_hydroxy-3-phthalimidoimidopropanamine; Nf group_3- (3,4-dimethoxyphenyl) dong g taiimidoimidopropanamide; 89179 -19- 200418455 3- (3-ethoxy-4-methoxyphenyl) -N-lightyl-3- (3-nitrophthaloamidoimino) propanamide; N- meso-3- (3,4-Dimethoxyphenyloxoisoindolyl) propanamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-('methyl- Phthamidamido) Propanamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthaloamidopropylamidoamine; 3- (3- Ethoxy-4-methoxyphenyl) _N_hydroxy-3 gas 1,3_dioxo_2,3_dihydro-1fluorene_benzo [f] isoeartholin-2-yl) propanamide ; N-Hydroxy-3- {3- (2-propoxyM-methoxyphenyl) 3-phthalimidoimidopropanamine; 3- (3-ethoxy-4-methoxyphenyl) -3- (3,6_difluorocarbamidoimino) · ν_hydroxypropionic acid amine; 3- (4-aminophthaloamidoimino) -3- (3-ethoxy-4_methyl Oxyphenyl) _N_hydroxypropylamidine; 3_ (3-aminophthaloamidoimino) -3- (3-ethoxy-4-methoxyphenyl) _ν_meridylpropylamidine; Ν- Isopropyl-3- (3,4-dimethoxyphenyl) _3_ (1_oxoisodecylyl) propanamine; 3- (3-cyclopentyloxy_4 · methoxyphenyl) _Ν Rhyme_3 isoxoisostilbamine, and N-benzyloxy 1 (3-ethoxy_4_methoxybenzylidene) propanamide. 4M3-nitropyridine The number of selective cells of the present invention includes inhibitory phenyl ethyl sulfone substituted with oxoisofluorinyl on phenyl 89179-20-20200418455. Examples of such compounds include (but are not limited to) them R5 disclosed in U.S. Patent No. 6,02,358

Y is 〇〇, ch2, s02 or ch2C = 〇; each of R1, r2, 3 and r4 are respectively hydrogen, commercial group, alkyl group of 4 to 4 carbon atoms, and 4 to 4 carbon atoms Alkoxy 3yl, 4nitro, cyano, hydroxyl or _NR8R9; or any of R1, R2, R3 and r45 on adjacent carbon atoms may form a fluorenylene group with the phenylene ring shown; each R5 and R6 are independently hydrogen, fluorenyl group of one carbon atom, carbon atom, alkoxy group, cyano group or cycloalkoxy group of up to 18 carbon atoms; Incorporated herein, including compounds of the following formula: wherein the carbon atoms marked with * constitute the center of the palm; R is a sulfonyl group, a fluorenyl group of one carbon atom, a phenyl group, a benzyl group, or an 8'r9, each R and R9 are independently hydrogen ,! An alkyl group, phenyl or benzyl group of 8 carbon atoms, or one of R8 and R9, x 7 8 9 is lice and the other is -COR10 or -S02R10, or & Methylene, butyl pentamethylene, hexamethylene or -CH2CH2X CH2CH2-, where χΐ is seven ... 9, or -ΝΗ-; and each RR is independently hydrogen, 1 to 8 Lutian f > 8, Q, atomic alkyl, phenyl or benzyl, or one of R8 and R9 'is-, 〇8, ^ 9, ,,, and two are -COR10, or -S02R10, Or R and R together form tetramethylene, οττ ^ ττ 2 pentamethylene, hexamethylene, or -CH2CH2X CH2CH2_, where: ^ is _s • or -ΝΗ-. 89179 -21-200418455 It is understood that although the above compounds are represented by phenethylsulfone for convenience, it includes sulfonamide when R7 is NR8'R9 '. Clear examples of these compounds are those in which γ is c == 0 or CH2. Another clear compound of these compounds is that each of R1, R2, R3 and R4 in their formula is independently hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxyl Or -NR8R9, each of which is independently hydrogen or methyl, and one of R8 and R9 is hydrogen, and the other is / 0CH3. A special compound is one of R1, R2, "and one of them in the formula is _NH2, and the remaining R1, R2, R ^ R4 is hydrogen. A special compound is one of their formula, R2, and R4 Is -NHCOCH3, and the remaining R1, R2, R3, and R4 are hydrogen. A special compound is -N (CH3) 2 in one of R1, R2, R3, and & Is hydrogen. Another preferred compound of these compounds is that in R1, R2, R3, and R4, one of them is a methyl group, and the remaining R1, R2, r ^ r4 are hydrogen. A special compound is their formula R2, R2, R2, R3, and R4 are hydrogen. One of R3 and R4 is fluorine, and 1 is nitrogen, methyl, pentyloxy, or cyclohexyl. The specific compounds are "and R6 is monoethyl, propyl'methoxy, ethoxy, propoxy, and oxy, respectively. Specific compounds are those in which R5 is methoxy, polycycloalkoxy and benzocycloalkoxy.

A methoxy group, R6 is a monocycloalkoxy group, and R6 is an ethoxy group. Methyl, ethyl, phenyl, 89179 -22- 200418455

Special compounds are those in which R7 is methyl, benzene, ethyl, phenyl, phenyl or NR8'9 ', wherein each of R8, and R9 is independently hydrogen or methyl. A particular compound is that in which R7 is methyl. A special compound is that in the formula, R7 is NR8,9, wherein each of R8, and R9 is independently hydrogen or methyl. Other well-defined selective cytokine inhibitory agents include fluoroalkoxy substituted 4 1,3-dihydro-isoindolyl compounds, which are disclosed in U.S. Provisional Application No. 60 / 436,975 (issued to G. Muller et al., Filed December 30, 2002), the disclosure of which is fully incorporated herein by reference. Representative fluoroalkyloxy-substituted 1,3-dihydro-isoindolinyl compounds include compounds of the formula:

Where: Y is -C (O)-, -CH2, -ch2c (o)-, -c (o) ch2-, or so2; Z is -Η, -C (0) R3,-(Coq-fe group) -S〇2- (Ci_4-alkyl), -Cn alkyl, -CH2OH, CHaOKCw alkyl) or -CN;

Ri and R2 are independently -CHF2, -Ci · 8 · antiyl, _C3.18 cycloalkyl or 1 (r alkyl) (C3-18-cycloalkyl), and at least one of 1 ^ and R2 is CHF2; R3 is -NR4R5, -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; R4 and R5 are independently -fluorene and -Cw alkane , -OH, -0C (0) R6; 89179 -23- 200418455 R6 is -Cm-alkyl, -amino (Cyalkyl), · phenyl, -benzyl or aryl; Xi, X2 , X3 and X4 are independently -H, -fluorene, -nitro, -NH2, -CF3, -Cw alkyl,-(C0_4-alkyl)-(Cw cycloalkyl), (Cw alkane Group) -NR7R8, (C0_4-alkyl) -N (H) C (0)-(R8), (C0-4-alkyl) -N (H) C (0) N (R7R8), (c〇_4_alkyl) _n (h) c (o) o (r7r8), (CG_4-alkyl) _or8, (Cg 4-alkyl) _imidazolyl, (CG-4_alkyl)- Pyrrolyl, (Cw alkyl) -pyridazolidyl or (Co alkyl) -triyl, or Xi, X2, X3, and X4 can be combined to form a cycloalkyl or heterocycloalkyl ring (For example: X2, χ2 and and, I and X3, X2 and X4, or X ^ X4 can form a 3, 4, 5, 6, or 7-membered ring, which can be aromatic, whereby and啕 p aryl ring forms a bicyclic ring system); and R and R are independently Η, Cn alkyl, c3-6 · cycloalkyl, (Cu-alkyl) _ (c3-6_cycloalkyl), ( cw alkyl) -n (r7R8), (Ci6 • alkyl) _〇r8, phenyl, benzyl or aryl; or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers thereof , Clathrate or prodrug. Preferred compounds of the present invention include (but are not limited to): 3- (4-ethylamidoamino-1,3-dioxoq,% dihydro_isofluorinyl) _3_ (fluorenecyclopropylmethoxy -4-difluoromethoxy-benzyl > propanoic acid; 3- (4-ethylamidoamino-1,3-dioxo 4,3 · dihydro_isopyridin_2_yl) _3 · (3_ propylmethoxy-4_difluoromethoxy-benzyl) _N, N_dimethyl · propanamide; 3- (4-ethylamidoamino_1,3_dioxy Generation 4,3_dihydro_isopyridine-2_ylcan 3_ (3-cyclopropylmethyllactyl-4-monofluoromethoxy-phenyl) _propionic acid amine; 3- (3-cyclopropyl Methoxy-4_difluoromethoxy_phenyl) winter (1,3_dioxo-1,3-dihydro-iso4-butor-2-yl) -propionic acid; 89179 -24- 200418455 3- (3-¾propylmethoxy-4-difluoromethoxy-phenyl) -3- (l, 3-dioxo-1,3-dichloro-iso-2-acyl-2-yl ) -N-Cyclopropylpropanamine; 3- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -3- (7-nitro-1-oxo-1,3 -Dihydro-isoindol-2-yl) -propionic acid methyl ester; 3- (3-cyclopropylmethoxy-4-difluoromethoxy_phenyl) -3- (7-nitro- 1-oxo-1,3 · dichloro-iso4 (l-2--2-yl) -propionic acid; 3- (3-cyclopropylmethoxy-4-di Methoxy-phenyl-3- (7-nitro-1-oxo-1,3-dihydro · isoindole-2-yl)-)-N, N-dimethyl · propanamide; 3- (7-amino-1-oxo-1,3-dihydro-isoearmidin-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy · benzene ) -N, N-dimethyl-propanamide; 3- (4-diaminomethyllactyl-3-ethoxy-phenyl) -3- (7-nitro-1-oxo-1 , 3-Dihydro-isoxazol-2-yl) -propionic acid methyl ester; 3- (7-amino-1-oxo-1,3-dihydro-isoxazol-2-yl) -3 -(4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester; 3- [7- (cyclopropanecarbonyl-amino) -1-oxo-1,3-dihydro -Isoindole-2-yl] -3- (4-dimethoxymethoxy-3 -ethoxy-phenyl) -methyl propionate; 3- (7_acetamido-1-lactone -1,3-dichloro-isoβ 丨 -2-yl) -3- (4-dimethoxymethoxy-3-ethoxy-phenyl) -propionic acid methyl ester; 3- (7-ethyl Alkylamino-1-oxo-1,3-dichloro-iso4 丨 hex-2-yl) -3- (4-diaminomethoxy-3-ethoxy-phenyl) -propionic acid ; 3-[7- (ί Screen propyl alkynyl-amino) -1 -oxo-1,3-diazine-iso-2-methyl] -3- (4-difluoromethoxy- 3-ethoxy-phenyl) -propionic acid; cyclopropanecarboxylic acid {2- [2-amine formamidine -1- (4-difluoromethoxy-3-ethoxy-phenyl) -ethyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl}-醯Amine; 89179 -25- 200418455 Cyclopropanecarboxylic acid {2- [l- (4-difluoromethoxy-3-ethoxy-phenyl) -2-dimethylamine formamyl-ethyl]- 3-oxo-2,3-dihydro-IH-isopyridin-4-yl}-; cyclopropanecarboxylic acid {2- [1- (4-difluoromethoxy-3-ethoxy-benzene ) -2-hydroxyaminomethylamidino-ethyl] -3-oxo-2,3-dihydro-1H-isoindole-4-ylpyridamine; 3- (7-ethylamidoamine -1-oxo-1,3-dihydro-isoxazol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propanamide; 3- ( 7-Acetylamino-1-oxo-1,3_dihydro-isoΘ 丨 hex-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl)- N, N-dimethyl-propanamide; 3- (7-ethylamidoamino-1-oxo-1,3-dihydro-isoamido-2-yl) -3- (4-di Fluoromethoxy-3-ethoxy-phenyl) -N-hydroxy-propylammonium; 3- (4-ethylamidoamino_1,3-dioxo-1,3-dihydro-iso 4 丨 Indol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid; 3- (4-ethylfluorenylamino-1,3-dioxo -1,3-dihydro-isoxanthenyl-2-yl) -3- (4-one gas methoxy -3-ethoxy) -propanamine; 3- (4-ethylamidoamino-1,3-dioxo-1,3-dihydro-isoamido-2-yl) -3- (4 -Difluoromethoxy-3-ethoxy-phenyl) -N, N-dimethyl · propanamide; 3- (4-ethylamidoamino-1,3-dioxo-1, 3-dihydro-isopyridin-2-yl) -3- (4-dimurylmethoxy-3-ethoxy-phenyl) -N-acryl-propylamine; cyclopropanecarboxylic acid { 2- [1- (4-Difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl] -3-lacto-2,3-diaza-l-iso 丨 丨- 4-yl} -pyrimidine; N- {2- [1- (4-diaminomethoxy-3-ethoxy-phenyl) -2-formyl-ethyl] -1,3- Dioxo-2,3-dihydro-1-isoamidine-4-yl} -acetamidine; and cyclopropanecarboxylic acid {2- [2-aminomethylamido-1- (4-difluoromethyl) Oxy-3-ethoxy · phenyl) -ethyl] -7-murine-3-oxo-2,3-diazine-1-iso-4-oxo-4-yl} -pentamine. 89179 -26- 200418455 Other selective cytokine inhibitory agents include 7-amido-substituted isordinyl compounds, shown in U.S. Provisional Application No. 60 / 454,155 (issued to G. Muller et al. , Filed on March 12, 2003), the disclosure of which has been fully incorporated herein by reference. Representative 7-fluorenyl-substituted iso-4-ole compounds include compounds of the following formula:

Where: Y is (: (0)-, -CH2, -CH2C (0)-or S〇2; X is Η; ζ is (C〇_4-alkyl) -C (0) R3, Cm- 垸Group, (C0.4-alkyl) -OH, (Ci-4-alkyl) -0 ((^-4-alkyl), (Cw alkylhSOKCM · alkyl), (C0-4- Alkyl) -SCKCw alkyl), (cG_4-alkyl) -NH2, (CG_4-alkyl) -NKCu-alkyl) 2, (C0_4-alkyl) -N (H) (OH), CH ^ SOKCm · alkyl); and R2 are independently alkyl, cycloalkyl, or-(Cm-alkyl) cycloalkyl, R3 is -NR4R5, -OH or -CKCu-alkyl); R4 is Η; R5 is _ΟΗ or _0C (0) R6; R is -Cn alkyl group, -amine group (Ci_8-alkyl group), (Ci-8-alkyl group)-(C3_6-carbyl group), C3- 6-cycloalkyl, phenyl, benzyl or aryl; or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers 89179 -27- 200418455 structures, clathrates or prodrugs ; Or a compound of the following formula.

Where: a Y is _C (0)-, -CH2, -ch2c (o) _, or s〇2; X is halogen, -CN, -NR7R8, -N〇2, or -CF3; W is

2 is (C0-4alkyl) 402 ((^-4-alkyl),-(C〇-4alkyl) -CN,-(Co-4alkyl) _C (〇) R3, Cm-alkane (CG_4-alkyl) OH, (CG.4-alkyl) 0 ((^. 4-alkyl), (C〇decylPOCCm-alkyl), (CG-4-alkyl) NH2 ((CG.4-alkyl) Nβυ-alkyl), (CG_4-alkyl) N (Η) (ΟΗ) or (C〇-4-alkyl) NSOKCm-alkyl); WS-C3_6-ring Alkyl,-(Cu-alkyl)-(C3-6cycloalkyl), _ (C〇-8-alkyl) -⑴3-6cycloalkyl) -NR7R8, (C〇-8-alkyl) -nr7r8, (CG_4-alkyl) -CHR9-pit group) -NR? R8, trans 1 and R2 are independently Cw alkyl, cycloalkyl or (Cw-alkyl) cycloalkyl; 89179 -28- 200418455 Let 3 be Cw alkyl, NR4R5, 〇 (cw alkyl); R and R5 are independently H, Ci 8-alkyl, (C (^ alkylHCw cycloalkyl), OH or -〇c ( 〇) r6; R is Cl · 8- ^ group, (CW alkyl group: KC3_6-cycloalkyl group), amino- (Ci-8-alkyl) 'phenyl group, benzyl group or aryl group; R7 and R8 They are independently H, Cy alkyl, (C alkyl alkyl hc3_6-cycloalkyl), phenyl, benzyl, aryl, or they can form a 3 to 7-membered heterocycloalkane with the attached atom Or heteroaryl ring; alkyl, (C (M_alkyl) aryl, (cw alkyl hC3 6 • cycloalkyl), (Cq-4 · alkyl) -heterocyclic; or pharmaceutically acceptable Accepted salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. Other selective cytokine inhibitors include N • alkyl_hydroxamate_isoamidine compounds' It is shown in US Provisional Application No. 60 / 454,149 (issued to G. Muller et al., Filed on March 12, 2003), the disclosure of which is fully incorporated herein by reference. Representative N_ Alkyl-isohydroxyribanoic acid-isoindolyl compounds include compounds of the formula:

Where: Y is -C (O)-, -CH2, -ch2C (〇) 4 s〇2; 1 ^ and R2 are respectively JL is CU8-alkyl, CF2H, CF3, CH2CHF2, naphthenic 89179 -29- 200418455 Or (Cm-alkyl) cycloalkyl, · ZA Η, Cw alkyl, _NH2-NR3R4 or OR5; Z2 is Η or C (0) R5;

Xi, X2, X3 and X4 are independently fluorene, halogen, N02, OR3, CF3, -c and 6-alkyl,-(C0_4-alkyl)-(C3_6-cycloalkyl), and (C〇_4_alkane) Group) _N (R8R9), (C〇-4-alkyl) -NHC (〇HR8), (c0.4-alkyl) -NHC (0) N (R8) (R9), (C0.4-alkane Group) -NHC (0) N (R8R9), (C〇-4-alkyl) -NHC (0) 0 (R8), (CG_4-alkyl) -o-r8, (cG_4-alkyl) -imidazole Group, (cG.4-alkyl) · pyrrolyl, (CG.4-alkyl) _biose, (C0_4_yl) -trimethyl or (Cw-alkyl) -hetero Ring; R3, R4 and R5 are each independently fluorene, Cw alkyl, O-Cu alkyl, phenyl, benzyl or aryl; R6 and R7 are independently Ci.6-alkyl; R · 8 and R9 They are independently fluorene, Cyfe group, C3 · 6 · ring total group, (Cn alkyl) _ (c3_6-cycloalkyl), (CG-6-alkyl) -N (R4R5), (Cu-alkyl) -〇R5, phenyl, benzyl, aryl, hexahydro P-pyridyl, hexahydro 7-p-pyridyl, erodolide, morpholinyl, or c3_7-heterocycloalkyl; or pharmaceutically acceptable Accepted salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. Specific selective cytokine inhibitory agents include (but are not limited to): 2- [1 Hepta-3 · ethoxy-4-methoxyphenyl) -2-methyl-sulfomethylethyl] isoammonium -1-one; 2- [1- (3 · ethoxy-4-methoxyphenyl) -2- (N, N-dimethyl-aminosulfonyl) ethyl] iso-4- -1-one; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] iso-4891891-30-30 200418455 Koulin-1,3 -Dioxin is the same; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -5-nitro-iso4 丨 laryn-1, 3 -Identical, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -4-nitroiso4 丨 laryn-1, 3-^-Pay, 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-aminoisoindolinline dione; 2_fM3- Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -5-methylisopropane-1,3-dione, 2- [1- (3-ethoxy -4-f-oxyphenylmethylphenethylethyl] acetamidoisoline 1-line-1,3-di-, 2- [1- (3-ethoxy-4-foxybenzene ) -2_methanesulfonylethylethyl'dimethylaminoiso4 丨 4 -1,3-di_, 2 ^-(3-ethoxy-4_f oxygen Group) _2_methyltransmethylethyl] -5 · dimethylaminoiso4 丨 Prin_1,3_ 二奶 2_ [H3-ethoxy-4-foxyphenyl) _2_methyl Sulfofluorenylethyl] benzoM iso-β-bordolin-dione; 2_ [Κ3-ethoxy-4-f like benzyl) _2_methylphenethylethyl] _4-methoxyiso 4 丨 Vinyl-dione; \ (3_cyclopentyloxy-4-foxyphenyl) _2 · methylcontinuous ethyl-amine; 2_ [H3-cyclopentyloxy- ^ oxyphenyl) -2 · Methylsulfonylethyl] isoxolinoline 1,3-dione; and 4 * -f-oxoyl) " " 2-Methylsulfonylethyl] -4- -Methyl 2- [1- (3_cyclopentyl-4 "monomethyl isothiophene? Isoline-1,3 monopyridine-31-89179 200418455 Other selective cytokine inhibitory Medicaments include those disclosed in US Patent No. 10 / 392,195 (filed on March 19, 2003); International Patent Application No. PCT / US03 / 0873 (filed on March 20, 2003); US Provisional Patent Application No. 6〇 M38,45〇 and 60 / 438,448 (issued to G. Jailer et al., Both of which were filed on January 7, 2003); and US Provisional Patent Application No. 60 / 452,46〇 (issued to G. Muller et al., Applied on March 5, 2003 ) Of the enantiomerically pure compound, the disclosure of these documents have been completely incorporated by reference herein. Preferred compounds include the enantiomers of 2- [1- (3-ethoxymethoxyphenyl) methylsulfonylethyl] -4-acetamidoisoindolinoline 4,3-: one Enantiomers of the compound and 3_ (3,4 · dimethoxy-phenyl) _3_ (i • oxo), 3_dihydro_isoindolyl) -propanamide. The preferred selective cytokine-inhibiting medicinal gas used in the present invention is 3_ (3,4_dimethoxy-phenyl) _3_ (1oxo_u_dihydro-isoselecyl) propylamidine With cyclopropanecarboxylic acid {2- [H3_ethoxy_4_methoxy_phenyl) _2_methanesulfonyl-ethyl] -3-oxo-2,3-dihydro._isoindole Indomethacrylamine, available from Celgene (Warren, NJ). The chemical structure of 3_ (3,4dimethoxy_phenyloxo-1,3-dihydro-iso4indol-2-yl) · propanamide is as follows: 0〆

Cyclopropanecarboxylic acid {2- [1 · (3-ethoxy_4_methoxy_phenyl) _methylene_ethyl] -3-oxo_2,3_dihydro_1Η · Isoamidine_4 • Gibmidine, its chemical structural formula is as follows: 89179 -32- 200418455

In the case of a compound named Ligongtu, it was disclosed in a patent case or a specialist in "Koumoto", "Moufa". This method can be synthesized by asymmetric synthesis, or it can be made using μ Prepared by other standard synthetic organic chemistry techniques. Master Chi Chi Wang and the salt used in this article unless otherwise stated, including salts mentioned in the term ^ Ego medically acceptable face. Can be accessed … Secretary n For organic and inorganic acids or bases known for toxic acid and base addition salts * Acids, phosphoric acids, sulfuric acid, formaldehyde ~ Including, for example: hydrochloric acid, hydrobromide ▲%, acetic acid 'tartaric acid citric acid, malic acid , Maleic acid, " ~ :, 7km ^ wood bismuth, aconic acid, 夂%, bismuth phthalate, pamoic acid, heptanoic acid, etc. Compounds with acidic properties can be used with a variety of medically acceptable The test results in the formation of salt. The tests that can be used to prepare these acidic compound salts are tangible ... the acceptable test additions on the second f ^, the parent alkaloid addition salts, which also contains medical Beautifully acceptable cations " earth metal salts, specific) gold test OR tests include (but are not limited to :: N: Di: or: ... choline, diethanolamine,? ... ylethylenediamine, chloroprocaine, rA * ethylene monoamine, methylglucamine (N -Methyl glucosamine), lysine and procaine .; otherwise the term "prodrug" refers to a biological condition (in vivo or Hydrolysis in vitro) 89179 200418455 to produce derivatives of the compound of the parent compound. Examples of prodrugs include (but are not limited to) · containing some groups that are biohydrolyzable, such as ... Hydrolyzed esters, biohydrolyzable urethanes, biohydrolyzable carbonates, biohydrolyzable ureas and derivatives of selective cytokine inhibitors of biohydrolyzable phosphate analogs. Others Examples of peony drugs include derivatives of selective cytokine inhibitory agents containing _N0, _N〇2, _〇N〇4 _〇NO2. These prodrugs are mainly prepared by conventional methods, As stated in i Burger, s Medicinal Chemis ”a: d Dr ug DiScovery, 172-178, 9-body 982 (edited by Μαη_Ε · 彻 打, 5th edition ‘1995), and Design 〇f Pr〇drugs (edited by

Elselvier, New York 1985). The terms "biohydrolyzable amidines and biohydrolyzable esters", "biohydrolyzable carbamates", "biohydrolyzable carbonate esters", unless otherwise stated, "," Biologically hydrolyzable ureas "and" Biohydrolyzable phosphates "refer to compounds such as amidine, esters, carbamates, carbonates, ureas, or phosphates. The compounds:丨) Does not interfere with the biological activity of the compound, but gives the compound beneficial in vivo properties, 々 Absorptivity, duration of action or start time of action; or 2) No biological activity: can be converted into biologically active compounds in vivo. Examples of biologically hydrolyzable compounds include (but are not limited to): low carbon number alkyl groups, low carbon number acid oxygen, alkyl alcohols (such as: ethyl acetate, ethyl acetate) , Aminocarbonyloxymethane :, Tentamyloxymethyl and Tentamyloxyethyl), lactone esters (such as: phthaloyl and: substituted phthaloyl esters), low-carbon alkoxyalkyloxyalkyl Esters (such as: methoxycarbonyloxy-ethoxyethoxyethyl and isopropoxycarbonyloxyethyl), alkoxyalkyl 89179 -34-200418455 esters, choline esters and amido alkyl esters (such as : Ethylaminomethyl). Examples of biohydrolyzable amidines include, but are not limited to, low carbon number alkylamidines, α-aminoacid amidines, alkoxyamidines, and alkylaminoalkylcarbonylamines. Examples of biohydrolyzable carbamates include, but are not limited to, low-carbon alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines With polyetheramines. Many selective cytokine inhibitory agents contain one or more palmar centers, and racemic or diastereomeric mixtures can occur. The invention includes the use of the pure stereoisomeric forms of these compounds and the use of mixtures of those forms. For example, mixtures of enantiomers containing equal or unequal amounts of selective cytokine inhibitory agents can be used in the methods and compositions of the invention. The purified (R) or (S) enantiomer of a clear compound disclosed herein may be substantially free of its other enantiomer. As used herein, and unless otherwise stated, the term "pure stereoisomerism" refers to one stereoisomer of a compound that includes substantially no other stereoisomer of the compound in the composition. For example, the pure stereoisomer composition of a compound with an opposing center is essentially free of the relative enantiomer of the compound. The pure stereoisomers of a compound with two palm centers are essentially free of other diastereomers of the compound. A typical pure stereoisomeric compound comprises about 80% by weight of one of the compounds and about 20% by weight of the compound, and more preferably about 90% by weight of the compound. A stereoisomer and other stereoisomers of the compound below about 10% by weight, even more preferably about 95% by weight of one of the compounds and about 5 weight 89179 -35- 200418455% of this compound Other stereoisomers of the compound. Most preferably, it is about 97% by weight or more of one of the stereoisomers of the compound and about 3% by weight or less of the other stereoisomers of the compound. As used herein and unless otherwise specified, the term "high stereoisomerism" refers to one of the stereoisomers of the compound that contains about 60% by weight or more, preferably about 70% by weight or more, and more preferably about One of the stereoisomers of the compound above 80% by weight. As used herein, and unless otherwise stated, the term "pure enantiomerism" refers to the pure stereoisomeric composition of a compound having one palm center. Similarly, "highly enantiomeric" refers to the highly stereoisomeric composition of a compound having an opposing center. It is understood that if the structural formula shown does not match the specified name, the structural formula presented will be the main one. In addition, if the stereochemistry or a part of the structural formula is not represented by, for example, a thick line or a dashed line, the structural formula or a part of the structural formula will include all of its stereoisomers. Second active agent The second active agent can be used in conjunction with a selective cytokine inhibitory agent in the methods and compositions of the present invention. In a preferred embodiment, the second active agent can inhibit or relieve the macula-damaged condition, produce an anti-angiogenic effect or an anti-inflammatory effect, or indeed make the patient comfortable. Examples of the second active agent include (but are not limited to): steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neutrophil factors, regulators of neovascularization, Anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds, anti-89179 -36- 200418455 vasomotor compounds, other agents known to inhibit or relieve MD symptoms, and their pharmaceutically acceptable salts and solvents Compounds, hydrates, stereoisomers, clathrates, prodrugs and pharmaceutically active metabolites. In some specific embodiments, the second active agent is phenanthrene, purlytin, angiostatic steroid, rhuFab, interferon-2α, or pentoxifylline. Examples of photosensitizers include ( But it is not limited to Fettfin, tin etiopurpurin and motexafin lutetium. Fitphen can be used to treat wet MD. Cour, M., et al. Drugs Aging 19: 101-133 (2002). Fitphen is a vascular blocking photoreactive dye that can be administered via injection. Examples of xanthine derivatives include, but are not limited to, pentoxifylline. Anti-VEGF antibodies include (but are not limited to): rhuFab. Examples of steroids include, but are not limited to, 9-Member-11,21-dihydroxy-16,17_1-methylethylenebis (oxy) pregnant-1,4-diene-3,20-dione. Examples of prostaglandin F2a derivatives include, but are not limited to: latanoprost (see U.S. Patent No. 6,225,348, the disclosure of which is fully incorporated herein by reference). Examples of antibiotics include (but are not limited to): tetracycline and its derivatives, rifamycin and its derivatives, macrolides and metronidazole (see US Patent Nos. 6,218,369 and 6,015,803, the disclosures of which have been Fully incorporated herein by reference). Examples of phytoestrogens include, but are not limited to: genistein, genistein, 6'-0-Mal genistein, 6'-0-Ac genistein, lignin isoflavones, daidzin, 6'_0_Mal daidzein, 6'-0-Ac soy taste, daidzein, glycidin, 6'-0-Mal daidzein, mesoflavone 89179 -37- 200418455 (biochanin) A, Formononetin and mixtures thereof (see US Patent No. 6,001,368, the disclosure of which is fully incorporated herein by reference). Examples of anti-inflammatory agents include, but are not limited to, triamcinolone and dexamethasone (see U.S. Patent No. 5,770,589, the disclosure of which is fully incorporated herein by reference). Anti-angiogenic compounds include (but are not limited to): thalidomide and selective cytokine inhibitory drugs (IMiDs ™, Celgene Corp., NJ). Examples of interferons include (but are not limited to): interference素 -2α. In another embodiment, the second active agent is glutathione (see U.S. Patent No. 5,632,984, the disclosure of which is fully incorporated herein by reference). Examples of growth hormones include (but are not limited to): basic fibroblast growth factor (bFGF) and transforming growth factor b (TGF_b). Examples of neutrophil factors include, but are not limited to, brain-derived neutrophil factors (BDNF). Examples of modulators of neoangiogenesis include, but are not limited to, fibrinogen activator type 2 (PAI-2). Other medicines that can be used to treat MD include (but are not limited to) EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and RETISERT implants (Bausch & Lomb Medicine 廒). Methods of treating prophylaxis The present invention includes methods of preventing, treating and / or treating a variety of MDs. -38- 89179 200418455 As used herein and unless otherwise exaggerated, M, π March, the term "prevention of MD,", "Treatment = and treatment of mediocrity, including (but not limited to) inhibiting or reducing one of _ related = The severity of the symptoms. Symptoms and related syndromes related to MD include (but limited to): the choroid of white-yellow gadolinium in the basement, discoid nodule tissue under the macula, the face of the pulse and even the veins ... the formation of pancreatic praying blood officers, retinal pigment epithelium. " Retinal pigment epithelium atrophy, long hemorrhage from the choroid (immediately below the retina rich vascular tissue layer), blurred vision or distorted vision, central blind spots, abnormal pigments, internal threads in the cloth A layer of fine-grained material is deposited and the Bruch film thickens and decreases permeability. As used herein, unless otherwise specified, the term "treating a woman" refers to the administration of a compound or other active agent of the present invention after the onset of symptoms of MD, where "prevention" refers to Patients at risk of MD) Administration. Patients at risk of MD "Examples of patients include (but are not limited to): seniors over 60 years of age and patients suffering from (but not limited to) · diabetes and leprosy (eg enl) Patients with a family history of MD are also good candidates for preventive therapy. As used herein and unless otherwise stated, the term "treating MD, including preventing MD recurrence and / or prolonging MD patients to maintain remission, is used." time.

The present invention includes methods for treating, preventing, and managing MD and related symptoms for patients suffering from different stages and specific disease patterns. The disease includes (but is not limited to): they are called dry MD, wet SMD, and related to aging. Macular degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelium detachment (PED), and retinal pigment epithelial atrophy (RPE). It further includes treating patients who have previously treated MD but have not responded to standard drugs and non-drug-based md treatments and patients who have not received MD treatment in the past. Because MD 89179 -39- 200418455 patients have many different clinical symptoms and many different clinical results, the treatment of patients may be different from time to time. Clinical experts who are familiar with this technology can determine specific secondary agents and treatments that can be used to effectively treat individual patients without undue experimentation. The methods encompassed by the present invention include administering one or more selective cytokine inhibitory agents or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, Shaped inclusion compound or prodrug. In a specific embodiment of the present invention, the recommended daily dose range of the selective cytokine inhibitory agent is about 1 mg to about 10,000 mg, which can be administered once a day in a single dose, or preferably divided into small doses Dosing in one day. More specifically, 'a day's dose can be divided into two equal portions and administered twice a day. The specific dosage range is about 1 mg to about 5,000 mg / day, about 10 mg to about 2,500 mg / day, about 100 mg to about 800 mg / day, and about 100 mg. mg to about [Mo post / day, or about 25 mg to about 2,500 mg / day. When treating patients, the therapy is first administered at a lower dose, which may be about 1 mg to about 2,500 mg, and if required, increased to about 200 mg to about 5,000 mg / day, which can be administered in a single dose, depending on the overall response of the patient , Or divided into small doses. In a specific embodiment, the dosage of Hong (3,4_dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindolyl) _propanamide is 400 per day , 800, 1,200, 2,500, 5,000 or 10,000 mg, divided into two doses. The treatment can last from about 2 to about 20 weeks, from about 4 to about 6 weeks, and from about 8 to about 12 weeks, until the desired effect is achieved or the desired effect can be maintained chronically. | Combination with a second active agent_ 法 89179 -40- 200418455, the method of the present invention includes the administration of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomerism物 i 元 口 口 物 or ㈤ 乐 and use a second active agent or active ingredient. Selective cytokine inhibitory drugs Nan Yu, Tiao Zhaobei 7F is disclosed in this book (see, for example, Section 4.1); and an example of a second active agent is also disclosed in this article (see, for example, Section 4 · 2 ). The selective cytokine inhibitory agent and the second active agent component selected as needed can be administered to the patient simultaneously or sequentially according to the same or different routes. The appropriateness of the particular route of administration of the full-featured active agent depends on the active agent itself (eg, whether it can be administered orally without decomposition before entering the bloodstream) and the disease being treated. The preferred route of administration of a selective cytokine inhibitory agent is oral or ocular administration. The preferred method of entertaining the second active agent of the present invention is known to those skilled in the art. See for example:

Physicians ’Desk Reference (57th edition, 2003). In a specific embodiment, the second active agent is administered orally, intravenously, intramuscularly, subcutaneously, transmucosally, topically or transdermally, once or twice daily, in an amount of about 1 mg to about 2,500 mg, About 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg. In another embodiment, the second active agent is administered weekly, monthly, every two months, or annually. The specific dosage of other active agents depends on the specific agent used, the type of MD being treated or prevented, the severity and stage of MD, and the amount of selective cytokine inhibitory agent currently used by the patient and any other agent selected as needed It depends. In a specific embodiment, the second 89179-41-200418455: the sex agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthomone derivative, a growth hormone, a neutrophil +, Neovascular effects, tinctures, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens / Xiaohuo compounds or anti-angiogenic compounds, or combinations thereof. f. Surgical intervention method This hair month includes a method for the treatment, prevention and / or treatment of MD, which includes administering & selective cytokine inhibitory agent or a pharmaceutically acceptable salt thereof, hydrate, sterol Structures, clathrates or prodrugs, and: (e.g., before, during, or after) surgical interventions. Surgical intervention methods, including (but not limited to) light or laser therapy, radiation therapy, retinal pigment epithelial transplantation and omental center displacement. Selective cytokine inhibition, medicaments and surgical methods, combined use, unique treatments & 'can bring unexpected results to some patients. Without being limited by theory, the salt-selective cytokine inhibitory agent can provide an additive or pro-active effect in parallel with surgical intervention. "In the specific embodiments, the present invention includes the treatment, prevention, and / or treatment of MD" Wanfa, "which includes administering an effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable drug to a patient in need thereof. Accepted salts, solvated sprues, stereoisomers, clathrates or prodrugs, and use light or field therapy. Examples of light or laser therapy include (but are not limited to): laser photocoagulation therapy Or photodynamic therapy. Yuandi 4 selective cytokine inhibitory agents can be performed simultaneously or sequentially with surgical intervention.-In a specific embodiment, selective cytokine inhibitory drugs are performed before light or laser therapy. Another- In the specific embodiment, the selectivity is 89179 -42- 200418455. The sex agent is performed after light or laser therapy.-Item specific two = selective cytokine inhibitory agent is under light or laser therapy: solid 2. 仃. Compounds can be administered at least four weeks before, two weeks before, one = or immediately before surgery or at the same time or after surgery, for a total of about 2 ** 16 weeks. In two specific embodiments, the present invention Preventive or cure The agent is a cyclic agent. Circulation therapy involves first administering the medicament for a period of time and then administering the drug to the back and / or the second medicament,] a period of car teeth slave time, and repeating this continuous administration process. Reduce its development resistance to one or more therapies, avoid or reduce the side effects of the eight middle therapy, and / or improve the therapeutic effect. : Indeed, in the specific embodiment, the 'prophylactic or therapeutic agent is administered cyclically for about 6 = about 1 or 2 times. One cycle may include the administration of a therapeutic agent or a prophylactic or prophylactic. The number of cyclic administration may be about 1 to ㈣ cycles, ′, 、, 土, 々 10 cycles, or about 2 to about 8 cycles. Compound and a single stern cymbal medicine composition can be used in individual single unit dosage forms. The present substance and dosage forms include selective cytokine inhibitory drugs :: di-salts too solvates, hydrates, stereoisomers, cages; package two: or Zele. The pharmaceutical composition and dosage form of the present invention can be used as excipients. However, the pharmaceutical compositions and dosage forms of the present invention may also include one or more other active clams. Therefore, the pharmaceutical composition and dosage form of the present invention include sexual agents (for example, selective cytokine inhibitory agents or their medicines; II 89179 -43- 200418455 H solvate, hydrate, stereoisomer prodrug and second activity剂). If necessary, select other, tongue: "the thing or the revealed (see for example: Section 42). ... sex clams such as the single invention of this text-unit dosage form suitable for oral, mucosal (such as: Lu, vagina, Intrabuccal or rectal) or parenteral (example: subcutaneous, static:,: Shimo Daimaru injection, intramuscular or intraarterial), bureau ', Qiaoru • eye music water), transocular, :: skin It can be administered to patients in a transdermal or transdermal manner. Examples of dosage forms include (but not limited to 人 人人 切 性 明 胶囊; a cachet; 锭 § tablets; a homogeneous solution; suppositories; powders; aerosols (such as ... Visual or inhalant); eye drops; gels; liquid dosage forms' including suspensions suitable for oral or mucosal administration to patients (for example: aqueous or non-aqueous liquid county suspensions: water-in-water emulsions or water-in-oil emulsions) Liquid solutions suitable for parenteral administration to patients; and sterile solids (such as crystalline or amorphous solids), which can be reconstituted into liquid dosage forms suitable for parenteral administration to patients. The composition, shape and type of the dosage form mainly depend on its use. For example: A dosage form for acute treatment may contain one or more active agents, the content of which is higher than the dosage form used for chronic treatment of the same disease. Similarly, the content of one or more active agents in parenteral dosage forms may be lower than that used. The content in oral dosage forms for the treatment of the same disease. The differences in these and other means included in the present invention are clearly understood by those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed. Mack Publishing , Easton PA (1990). Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients 89179 -44-200418455 are those skilled in the art of pharmaceuticals and suitable excipients. Examples of limitations are provided herein. Whether a particular excipient is suitable for addition to a pharmaceutical composition or dosage form depends on a number of factors known in the relevant art, including (but not limited to) the manner in which the dosage form is administered to the patient. For example : Excipients contained in oral dosage forms such as lozenges may not be suitable for parenteral dosage forms. The suitability of specific excipients also depends on the dosage form It depends on the active agent. For example, some active agents can be accelerated by some excipients (such as lactose) or can be accelerated when exposed to water. Active agents containing primary or secondary amines are particularly vulnerable to such accelerated degradation. Therefore, in addition to the monosaccharides or disaccharides, the pharmaceutical compositions and dosage forms included in the present invention may contain (if included) a small amount of lactose. As used herein, the term "lactose-free" means if any lactose may be contained in an insufficient amount To substantially increase the degradation rate of the active agent. The lactose-free composition of the present invention may include excipients known in the related art, which are shown in US Pharmacopeia (USP) 25-NF20 (2002). Generally speaking, The lactose-free composition comprises a pharmaceutically compatible and pharmaceutically acceptable content of an active agent, a binding agent / filler, and a lubricant. Preferred lactose-free dosage forms include the active agent, microcrystalline cellulose, pregelatinized starch, and magnesium stearate. The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing active agents because water can cause the degradation of certain compounds. For example, the addition of water (eg: 5%) is a method widely accepted in medical technology for simulating long-term storage conditions to determine the shelf life or stability of formulations over time. See, for example, Jens T. Carstensen, Drug Stability Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat can accelerate the degradation of certain compounds. Therefore, the effect of water on the formulation is very serious -45- 89179 200418455 It is because of the manufacture, operation, sentence, and two plus of the formulation that the storage and transportation of toilets are often encountered with moisture and / or humidity.典 The Code of Water Pharmaceutical Compositions and Dosage Forms of the Ming Dynasty, Xi Shi A Tu J ^ The conditions of sowing with water or low water content to make a knife and the conditions of low moisture and low humidity are invited to "Medical Preparations and Dosage Forms of Medical Preparations at Noon 3" In the case of at least one active agent containing a secondary or secondary amine, if two = water will be encountered during manufacturing, packaging, and / or storage, it is preferably an anhydrous form. Preparation of anhydrous pharmaceutical compositions and Storage # should maintain its anhydrous nature. Because the anhydrous composition is best packaged with a material that is known to be waterproof, so that it is limited to the set of weekly formulations. Examples of suitable packaging include (but not seven seals) m. Plastic, unit-dose containers (such as blister packs and long packs). Known = inventions, including one or more kinds of medical substances that can reduce the degradation rate of the active agent "medical composition and dosage forms. These compounds are described herein. It is called "Ann includes (but is not limited to): antioxidants, such as ... ascorbic acid, pH buffer or salt buffer. As the amount and type of excipients, the dosage and specific types of active agents in the dosage form may depend on , Such as · 々, 3 · Suding patients < Factors and other factors. However, the typical example of the present invention is: 刑 丨 # 4 人 #, 匕 §Selective cytokine inhibitory agent or its medically acceptable _%, ,, wind nine, drop agent, hydration Compounds, stereoisomers, clathrates, or prodrugs, which are used for reinstatement, about 1 to about 10,000 mg. Typical dosage forms include selective cytokines II 〃, 、,, or pharmacological inhibitors Acceptable salts, solvates, hydrates, corpus isomers, dragon-shaped inclusion compounds or prodrugs, the content of which is about 2, 5 ,! nq 10, 25, 50, 100, 200, 400, 800, 1,200, 89179 -46- 200418455 2,500, 5,000, or 10,000 mg. In specific embodiments, preferred dosage forms include 3- (3,4-dimethoxy · phenyl) -3- (1-oxo -1,3-dihydro-isoindole-2-ylpropanamine, which is present at a level of about 400, 800 or 1,200 mg. A typical dosage form contains a second active agent at a level of about 1 to about 2,500 mg, About 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg. Of course, the second activity Of The exact dosage will vary depending on the specific medicament used, the type of MD being treated or treated, and the selective cytokine inhibitory medicament, and the amount of any other active agent selected for concurrent administration to the patient as needed. The pharmaceutical composition of the present invention for oral administration may be in separate dosage forms, such as (but not limited to) ... lozenges (eg, chewable tablets), film-coated tablets, capsules, and liquids (eg, flavored syrup). These dosage forms include predetermined The amount of active agent can be prepared according to methods known to those skilled in the art of pharmacy. See generally Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990). A typical oral dosage form is prepared by uniformly mixing an active agent and at least one excipient according to a conventional pharmaceutical compounding technique. Excipients can take many forms, depending on the type of formulation required. For example, excipients suitable for oral liquids or aerosols include (but are not limited to): water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for solid oral dosage forms (such as powders, lozenges, capsules and film-coated tablets) include (but are not limited to): starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, Binders and disintegrants. -47- 89179 200418455 Because tablets and capsules are convenient for administration, they represent the most advantageous oral unit dosage form. In this case, solid excipients are used. If necessary, the tablets can be coated with standard aqueous or non-aqueous techniques. These dosage forms can be prepared by any pharmaceutical method. Generally, pharmaceutical compositions and dosage forms are prepared by uniformly mixing the active agent with a liquid carrier, a uniformly dispersed solid carrier, or both, and then, if necessary, forming the product into a desired formulation. For example, the method of making pastilles can be compressed or die-cast. Compressed tablets are prepared in a suitable machine by compressing the active agent in a free-flowing form, such as powder or granules, and mixing it with excipients as needed. Moulded ingots are prepared by moistening powdered compounds with an inert liquid diluent in a suitable machine. Excipients that can be used in the oral dosage form of the present invention include, but are not limited to, a binding agent, a filler, a disintegrant, and a lubricant. Suitable binding agents for pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural gums and synthetic gums, such as acacia gum, sodium alginate, alginic acid, others Alginate, powdered tragacanth, guanhua bean gum, cellulose and its derivatives (e.g. ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), Polyethylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (eg, · nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold under the names AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. The clear binding agent is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, which is sold under the name -48 · 89179 200418455 of AVICEL RC-581. Suitable helmets for permanent M people ... Low-moisture excipients or additives include AVICEL_PH_103 and starch 150 LM. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, rhenium carbonate (eg, granules or powder); microcrystalline cellulose, cellulose powder, dextran, kaolin, mannitol , Oxalic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. A typical content of the binder or filler in the pharmaceutical composition of the present invention is about 50 to about 99% by weight based on the weight of the pharmaceutical composition or dosage form. / The tablet # formed by using a disintegrant in the composition of the invention will disintegrate when exposed to an aqueous environment. Lozenges containing too much disintegrant may disintegrate during storage and too little, and may not disintegrate at the required rate or under the required conditions. Therefore, the amount of the disintegrant should be sufficient, not too much or too little, so as not to change the amount of the disintegrant that is used in the formation of the solid oral dosage form of the present invention. Related skills = easy to understand. A typical pharmaceutical composition contains from about 0.5 to about 15% by weight of a disintegrant, and from about 5 to about 5% by weight. / () Disintegrant is preferred. Disintegrating agents that can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, general Carboline (poiacrilin), sodium starch glycolate, potato or cassava starch, other starch, pregelatinized starch, other starch, clay, other alginic acid, other cellulose, gum and mixtures thereof. Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include (but are not limited to): calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol Alcohols, other glycols, stearic acid, 89179 -49- 200418455 sodium lauryl sulfate, talc, hydrogenated vegetable oils (for example: peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), hard Zinc stearate, ethyl oleate, ethyl laurate, agar and mixtures thereof. Other lubricants include, for example: Silicate Silicone (AEROSIL 200, manufactured by WR Grace Co., Baltimore, MD), Condensing Aerosols of Synthetic Silica (sold by Degussa Co. of Piano, TX), CAB SIL (pyrolytic silica product, sold by Cabot of Boston, MA) and mixtures thereof. When used, lubricants are typically used at less than about 1% by weight of the medical composition or dosage form. The preferred solid oral dosage form of the present invention includes a selective cytokine inhibitory agent, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous stone stone and gelatin. Sustained release

… ~ M has just been used to control drug delivery methods or delivery devices known to those who are not familiar with them.丨 Examples include (but are limited to): they were stated in US patent case numbers: 3,845,770; 3,916,899; 3,536,8〇9: = ^ and 4 Ze, 719, 5,674,533, 5 () 59,595, 5,591,767-^ ' 548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, which is equal to the valley, and it is used! The formula is fully incorporated herein. These dosage forms can be used in membranes, osmotic systems, multilayer coatings, and microparticles; 1 masterbatches, gels, and samarium combinations' are used to provide slow-release or controlled-release microspheres for different proportions of desired release patterns. A variety of active agents' appropriate controlled release formulations (including those in this head _ related technology known to choose active agents to choose and use. The present invention therefore contains: =) can easily be combined with "including controlled release Single unit dosage forms suitable for oral administration 89179 -50 · 200418455 such as capsules (gelcaps) and film-coated tablets. (But not limited to) bonding agent capsules, gelatin All controlled release pharmaceutical products have an uncontrolled release equivalent The effect of the drug is its controlled release system, which is optimally designed: therapies include prolonged drug activity, reduced dosing frequency, and improved patient suitability. = Package, system, and the formulation can be used for the initiation of shadow application Or other characteristics, 'Mouth. Musical "blood concentration, which can affect the use of side effects." Xiaogentian 丨 the design of most controlled release formulations for the first release-sex boat, promote the production of required Continuous release gradually after therapeutic effect 1: Other (the amount of the tongue's pleasure 'to maintain this therapeutic or preventive effective amount of the drug-for a period of time. In order to maintain the μ amount of this drug in the body, the rate of drug release in the dosage form must be Replacement drugs in vivo And the rate of excretion. The controlled release of the active agent can be stimulated by a variety of conditions, including (but not limited to): ρΗ, temperature, enzymes, water or other physiological conditions or compounds. It is administered to patients in many different ways, including (but not limited to) · intravitreal, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial. Because its administration method mainly bypasses the patient's natural defense against foreign objects System, parenteral dosage forms are preferably sterile or can be sterilized before administration to patients. Examples of parenteral dosage forms include (but are not limited to) · ready-to-use solutions for injection, ready-to-use for dissolution or suspension in Pharmaceutically acceptable 89179 -51- 200418455 Dry products for injection vehicles, ready-to-use injectable suspensions, and emulsions. Suitable vehicles for providing parenteral dosage forms of the present invention are those skilled in the art. Examples include (but not limited to): USP for injection; aqueous vehicles such as (but not limited to): sodium chloride injection, Ringerf's injection, Dextrose injection, dextrose and sodium chloride injection, and Ringer's injection with lactic acid; vehicles that are miscible with water such as (but not limited to): ethanol, polyethylene glycol, and polypropylene glycol; and Non-aqueous vehicles such as (but not limited to): corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. It can also be used in parenteral dosage forms of the present invention. Add compounds that increase the solubility of one or more active agents. For example, cyclodextrin and its derivatives can be used to increase the solubility of selective cytokine inhibitory agents and their derivatives. See, for example, U.S. Patent No. 5,134,127, which The disclosure is fully incorporated herein by reference. Topical and mucosal dosage forms The topical and mucosal dosage forms of the present invention include (but are not limited to): eye drops, sprays, aerosols, solutions, emulsions, suspensions, or habitually Other types known to those skilled in the art. See, for example: Remington's Pharmaceutical Sciences, 16A and 18th eds, Mack Publishing, Easton PA (1980 &1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed, Lea & Febiger, Philadelphia (1985). Formulations suitable for treating oral mucosal tissues can be formulated into mouthwash or oral gel. Suitable excipients (eg, carriers and diluents) and other substances that can be used to form the topical and mucosal dosage forms encompassed by the present invention are those known to those skilled in the art -52- 89179 200418455 and will Depending on the particular tissue to which a given pharmaceutical composition or dosage form is administered. Examples of typical excipients include (but are not limited to, non-toxic emulsions or gels that are non-toxic and pharmaceutically acceptable. Receptive acetone, ethanol, ethylene glycol, propylene glycol, butane 4,3-diol , Butan Ⅱ Nikoshi Bismuth propyl ester, Xing propyl palmitate, mineral oil and mixtures thereof. If necessary, we can add wetting agents or humectants to pharmaceutical compositions and dosage forms. This sign d soil τ Examples of other components of this temple are known to those who are familiar with this technology. I see, for example: Remingt〇n, s

Pharmaceut1 Cal Sciences, 16 ^ 18-eds., Mack Publishing, Easton PA (1980 & 1990). It is also possible to adjust the pH of the pharmaceutical composition or dosage form to improve one or more of the ingredients: specific delivery. Similarly, the polarity of the solvent carrier, its ionic strength, or isotonicity can be adjusted to & improve transportability. It is also possible to add compounds such as stearates to the pharmaceutical composition or dosage form, which is beneficial to change the hydrophilicity or lipophilicity of one or more active agents, and to improve the transportability. In this case, stearates can be used as a lipid vehicle, emulsifier or surfactant for the formulation and as a transport enhancer or penetration enhancer. Different salts, hydrates or solvates can be used to further adjust the properties of the resulting composition. The kits and the active agents of the present invention are preferably not administered at the same time or are preferably not administered in the same way. Therefore, when the kit covered by the present invention is operated by medical personnel, the process of administering an appropriate amount of active agent to a patient can be simplified. The present invention < typical kit includes a dosage form of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, peony or clathrate. The kit of the present invention may further comprise 89179-53-200418455 or more other active agents or a combination thereof. Examples of other active agents have been disclosed herein (see, e.g., Section 4.2). -The kit of the present invention may further include a device for administering the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches and inhalers. The kit of the present invention may further include an Amsler grid suitable for detecting or diagnosing MD. The kit of the present invention can further comprise a pharmaceutically acceptable vehicle that can be used for seeding or multiple active agents. For example, if the active agent is in a solid form, it must be reconstituted for parenteral administration. The kit may include a sealed container containing a suitable vehicle, wherein the active agent can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. . Examples of pharmaceutically acceptable vehicles include (but not limited to, um vehicles for water injection such as (but not limited to): sodium chloride injection, Ringer's (Ringer's) injection, dextrose injection, right Rotary sugar, chlorinated fishing injection, and Ringer's injection with lactic acid; vehicles that are miscible with water such as (but not limited to): ethanol, poly-r-ethylene glycol and polypropylene glycol; and non-aqueous vehicles such as ( (But not limited to): corn oil, cottonseed oil, peanut oil, sesame oil, bismuth ethyl oil, isopropyl myristate and benzyl benzoate. Examples The following examples further illustrate the in vitro pharmaceutical analysis method without limiting the present. The scope of the invention. Selective cytokine inhibition_ &…; Li Wang's effect is to reduce TNF-oc. Special selective cells

The hormonal inhibitory agent can enhance the TNF mRNA P Liye. TNF-α may play an important role in the pathogenesis of plaque degeneration only in dragons. In this specific example, it is discussed in the in vitro test of 3- (3,4-dimethylamino) in vitro. 89179- Pharmacological properties of 54-200418455-phenyl-phenyl) -3. (1-oxohydro-isoeardodolyl) propanamide. The child test measures the effects of this compound on the production of various cytokines. The effect of compounds in inhibiting the production of TNF-α by human pBMC and human whole blood stimulated by Lps was investigated in vitro. In vitro tests show that the pharmacological activity of 3_ (3,4_dimethoxy · phenyl) -3- (1-oxo-1,3-dihydro_iso ... dodonyl) _propanamide is bisal Ricci is 5 to 50 times stronger. The effect of 3_ (3,4_dimethoxy-phenylpyridineoxo-1,3-dihydro-isoindol-2-yl) _propanamide may be derived from its inhibition of inflammatory hormone production effect. The clinical reading of MD patients with plaque'k patients has a selective cytokine inhibitory dosage of about 20 to about 1200 mg per day. In a specific embodiment, the clinical trial is performed by 40 patients with macular degeneration divided into two groups. The first group received treatments that traditionally used Fettenven's photodynamic therapy to seal leaky choroidal vessels (a characteristic of this disease). Ophthalmol 1999 (117): 1329-1345. The second group received the same traditional therapies with Fettphene and about 20 mg / day of (+)-241 (3-ethoxy-4 · methoxyphenyl) -2-methylcontinylethyl ] Acetylaminoisoindolinoline 1,3 · dione as adjuvant for 20 weeks. Accept (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4_ethylamidoaminoisoxolinolinone The experimental group fully suppressed a series of neovascular reactions and prolonged the effect of photodynamic therapy indefinitely. However, (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetamidoaminoisoindole was not used In the first group of phthaloline-i, 3-dione, re-perfusion occurred in the treated blood vessels several weeks after the treatment. He gradually lost vision and needed to repeat photodynamic therapy. In other preferred embodiments, (+)-2- [1- (3-ethoxy-4-methoxybenzene 89179 -55- 200418455) -2-methylsulfonylethyl] -4 -The dosage of ethanoylaminoiso-β-doline-1,3-diazepine I is about 1 to about 200 mg / day, preferably about 10 to about 50 mg / day, or two doses, usually per Use about 1.5 to 2.5 times the daily dose every other day. Adjuvant therapy is applicable to other traditional therapies for the treatment or prevention of MD, including (no, human, and: surgical intervention methods, including laser-induced coagulation. The specific embodiments of the present invention are only for illustrating the scope of the present invention. ..., and it is revealed that the inner concubine has been fully incorporated by reference into 89179 56-

Claims (1)

200418455 Scope of patent application: L-A method for treating, preventing or treating macular degeneration, which includes the treatment, prevention or treatment of patients who are effective for the treatment or prevention: a selective cytokine inhibitory agent or its predominant drug Accepted solvates or stereoisomers. 2. The method according to item 丨 of the patent application scope, which further includes administering to the patient a therapeutically or prophylactically effective amount of a second active agent. Q 3. The method according to item 2 of the scope of the patent application, wherein the first: active ^ is ~ sterol, photosensitizer, integrin, antioxidant, interferon, Huang Yin: hormone derivatives, growth hormone, chemotactic Neutrophil factors, modulators of neovascularization, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds. 4. The method according to item 2 of the scope of patent application, wherein the second active agent is thalidomide, vefinol, purlytin, angiostatic steroids, rhuFab , Interferon or pentoxifymne, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 5. The method according to item 4 of the application, wherein the anti-angiogenic compound is thalidomide. 6. The method according to item 1 of the scope of patent application, wherein the macular degeneration is wet-type macular degeneration, dry-type macular degeneration, aging-related macular degeneration, aging-related macular degeneration, choroidal neovascularization, and retinal pigment epithelium dissection Retinal pigment epithelium atrophy, Best disease (Best, s diSeaSe), yolk type, Surgardfs disease, juvenile 89179 200418455 Soil κ spot will support P, basal macula, Bell's disease (Behr, s disease), Sorsby's disease, Doyne's disease, honeycomb dystrophy or macular damage. 7. The method according to item 丨 of the patent application scope, wherein the selective cytokine inhibitory agent is pure stereoisomerism. 8. A method of treating, preventing or treating macular degeneration, comprising administering to a patient in need of such treatment, prevention or treatment a therapeutically or preventively effective amount of 3- (3,4-dimethoxy-phenyl) _3 Serving as q-sense dihydro_isopyridin_2_yl) propanamide or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 9. The method according to item 8 of the scope of patent application, wherein the 3- (3,4-dimethoxyphenyl) 3 (1-oxo_1,3_dihydro-isoindolyl) propanamide It is purely enantiomorphic. Method for preventing or treating macular degeneration, comprising administering a therapeutically or preventively effective amount of iridium propanecarboxylic acid {2_ [1- (3-ethoxy_ 4_methoxy_phenyl) _2_methanesulfonyl = yl] -3-oxo_2,3-dihydro-1H-isopyridin-4-ylbutanil or its pharmaceutically acceptable Salts, solvates or stereoisomers. U. The method according to item 10 of the patent application, wherein the {2_ [ethoxy ^ methyl-phenyl) -2-methanesulfonyl · ethylbuoxo_2,3_dihydro Isoindol-4-ylbutramine is pure enantiomer. According to the method described in the “Scope of Patent Application”, the selective inhibitory agent is as shown in formula (1): It prime 89179 200418455 (i) where n is 1, 2, or 3; R5 is orthophenyl, unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of nitro, cyano, Trifluoromethyl, ethyl, methyl, propyl, ethyl, carbamoyl, ethoxy, carboxy, hydroxy, amine, alkylamino, dialkylamino, fluorene Amine group, 1 to 10 hindering alkyl group, 1 to 10 carbon atom alkoxy group, and halo group; R7 is (i) phenyl or one or more groups independently selected from the group consisting of Substituted phenyl groups: nitro, cyano, trifluoromethyl, ethyl, methyl, propyl, ethyl, carbamoyl, ethoxy, carboxy, hydroxy, Amine group, alkyl group of 1 to 10 carbon atoms, alkoxy group of 1 to 10 carbon atoms, and _ group; (ii) benzyl, which is unsubstituted or selected from i to 3 Substituents in the group consisting of nitro, cyano, trifluoromethyl, ethyl, methyl, propyl, ethyl, carbamoyl, ethoxy, ethoxy, Several amines, amines, 1 to 0 Son alkyl group, alkoxy having 1 to 10 carbon atoms of the group, and! | Group; (iii) fluorenyl group; and (iv) benzyloxy group; R12 is -OH, alkoxy group of 1 to 12 carbon atoms or / R8 —N, R9 R8 is hydrogen or 1 to 10 carbon atoms Hydrazone, and 89179 R is hydrogen, an alkyl group of 1 to carbon atoms, -COR1G or -S02R1G, which is oxygen, an alkyl group of 1 to 10 carbon atoms, or a phenyl group. According to the method of claim 12, the selective cytokine inhibitory agent is purely enantiomeric. The method according to item 1 of the scope of patent application, wherein the selective cytokine inhibitory agent is represented by formula (II): 0 R1 11 R3, 0R2 R (CpH ^)-C-N-O-R4 R4, where each R1 When it is independent from R2, it is hydrogen, a low-carbon alkyl group, or R1 and R2 can form an ortho-phenyl group, ortho-phenylene group, or cyclohexene-1,2-diyl group together with the carbon atoms to which they are respectively bonded. Unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of nitro, cyano, trifluoromethyl, ethyl, methyl, propyl, and ethyl , Carbamate, ethyloxy, carboxyl, hydroxy, amine, alkylamine, dialkylamine, donkeyamino, alkyl of 1 to 10 carbon atoms, to 10 carbon atoms Alkoxy and alkoxy; R3 is phenyl substituted by 1 to 4 substituents independently selected from the group consisting of: nitro, cyano, trifluoromethyl, ethyl, and methyl , Propyl ester 'ethenyl, carbamate, ethenyloxy, carboxyl, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, 1 to 10 Atomic alkylthio, benzyloxy, 3 to 6 carbon atoms cyclic anti-milk group, C4-C6-% ^ alkylene methyl, C3-Cio-alkylene methyl, manganese 89179 200418455 Oxygen and radical; R4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R4 is hydrogen or alkyl of 1 to 6 carbon atoms; R is -CH2-, -CH2- CO-, -S02-, -S- or · NΗ (: 0-; and the value of n is 0, 1 or 2. According to the method of claim 14 of the patent scope, the selective cytokine inhibitory agent It is pure enantiomerism. This method is based on the patent claim g, wherein the selective cytokine inhibitory agent is represented by formula (III): R5 m Among them, the carbon atom marked with * constitutes the center of palm; ¥ is C = 〇, CH2, S〇2, or CH2C = 〇; each R, R, R3, and R4 are independently hydrogen, halo, i to 4 Carbon atom < alkyl, alkoxy group of 1 to 4 carbon atoms, nitro, cyano, hydroxyl or -NR8R9; or any one of R1, R2, "and R4 on adjacent carbon atoms may be the same as shown The phenyl ring together forms a fluorenylene group; each of R5 and R6 is independently hydrogen, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 4 to 4 carbon atoms, a cyano group, or an alkyl group of up to 18 carbon atoms. Cycloalkoxy; R is benzyl, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, NR8'R9 '; 89179 2〇418455, each of R8 and R9 is independently hydrogen and ⑴ carbon Atomic alkyl, phenyl or benzyl or one of R and R is hydrogen, the other is _c〇r10 or _s〇2Ri〇 or R8 and R9 together form tetramethylene, pentamethylene , Hexamethylene or, where X is _〇 ~ s or mystery; and #each RR knife is independently hydrogen, alkyl group of 8 to 8 carbon atoms, phenyl or winter methyl group or R8 and R9 One is hydrogen and the other is -COR10, or -S02R10 'or R8' and R9 ' Forms tetramethylene, pentamethylene, hexamethylene, or -CH2CH2X2CH2CH2_, where X2 is -0 ·, _s_, or _NH. 7. According to the method in item 4 of the patent No. 16 in Zhong 4 Sex cytokine inhibitory agents are pure enantiomers. 18 · —Methods for the treatment, prevention or treatment of macular degeneration, including those patients in need of such treatment, prevention or treatment, in order to reduce or avoid $ A therapeutic or prophylactically effective amount of a selective cytokine inhibitory agent or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered before, during, or after a surgical intervention for macular degeneration symptoms. The method of item 17 of the patent scope includes operative interventions in the middle stage of light therapy, laser therapy, radiation therapy, retinal pigment epithelium transplantation, or omental center displacement. • Ile composition comprising a selective cytokine inhibitory agent Or it can be combined with double salts, solvates or stereoisomers, and a second active agent that can reduce or avoid the symptoms of macular degeneration. 21. The pharmaceutical combination according to item 20 of the patent application park Wherein the second active agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrophil factor, a regulator of new blood organ formation, and an anti-VEGF Antibodies, prostaglandins, antibiotics «Q17Q 200418455, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds. 22. The pharmaceutical composition according to item 20 of the patent application scope, wherein the second active agent is thalidomide ( thalidomide), verteporfin, purlytin, angiostatic steroids, rhuFab, interferon-2α or pentoxifylline, or pharmaceutically acceptable salts, solvates or stereo Isomers. RQ17Q 200418455 Dyeing and designated representative drawings: (1) The designated representative drawings in this case are: (none) (II) The representative symbols of the representative drawings are briefly explained: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention : 〇 〇 II C 0 II Ν— CH— (CnH 2n) ~ C— R12 R7 H m 89179 -4-